研究者詳細 - 武市　拓也

KLICK Syndrome Linked to a POMP Mutation Has Features Suggestive of an Autoinflammatory Keratinization Disease 国際誌

長島型掌蹠角化症とアトピー性皮膚炎が併存した1例

垣生美奈子, 武藤潤, 藤井由美子, 吉川剛典, 武市拓也, 秋山真志, 佐山浩二

日本皮膚科学会雑誌 130 巻 ( 5 ) 頁： 1191 - 1191 2020年5月

Takeichi, T; Akiyama, M

FRONTIERS IN IMMUNOLOGY 11 巻頁： 641 - 641 2020年4月

記述言語：英語出版者・発行元：Frontiers in Immunology

Keratosis linearis with ichthyosis congenita and sclerosing keratoderma (KLICK) syndrome is a rare autosomal recessive skin disorder characterized by palmoplantar keratoderma, linear hyperkeratotic plaques, ichthyosiform scaling, circular constrictions around the fingers, and numerous papules distributed linearly in the arm folds and on the wrists. Histologically, the affected skin shows hypertrophy and hyperplasia of the spinous, granular, and horny epidermal layers with mild infiltration of inflammatory cells in the upper dermis. There are 14 patients with KLICK syndrome described in the literature, and they all carry the same nucleotide deletion. Proteasome maturation protein (POMP), encoded by POMP, is an ubiquitously expressed protein that functions as a chaperone for proteasome maturation. KLICK syndrome is caused by a reduction in POMP levels that leads to proteasome insufficiency in differentiating keratinocytes. It is noteworthy that POMP is also known to be the causative gene for proteasome-associated autoinflammatory syndrome-2 (PRAAS2). It is considered that the disrupted proteasome assembly caused by the POMP mutation might lead to both skin inflammation and then hyperkeratosis in KLICK syndrome. Inflammation caused by the hyperactivation of innate immunity occasionally leads to inflammatory diseases of the skin, recently denoted as autoinflammatory keratinization diseases (AiKDs). We propose that KLICK syndrome caused by the specific 1-bp nucleotide deletion mutation in the regulatory region of POMP might be in a spectrum of proteasome-associated phenotypes.

DOI： 10.3389/fimmu.2020.00641

Frequent FOXA1-Activating Mutations in Extramammary Paget's Disease 査読有り国際誌

Takeichi, T; Okuno, Y; Matsumoto, T; Tsunoda, N; Suzuki, K; Tanahashi, K; Kono, M; Kikumori, T; Muro, Y; Akiyama, M

CANCERS 12 巻 ( 4 ) 2020年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Cancers

Extramammary Paget’s disease (EMPD) is a neoplastic skin disease of indeterminate origin with an unknown genetic cause. We performed a comprehensive genetic analysis or targeted gene sequencing in 48 patients with EMPD. We identified FOXA1 mutations, a GAS6–FOXA1 fusion gene, and somatic hotspot mutations in the FOXA1 promoter region in 11 of the 48 EMPD patients (11/48, 23%). Additional mutations were identified in PIK3CA (six patients) and in HIST1H2BB, HIST1H2BC, and SMARCB1 (one patient each), but none were found in other frequently mutated genes in cancer. A global gene expression analysis using EMPD clinical samples found the upregulation of PI3 kinase–AKT–mTOR signaling. ABCC11, which is specifically expressed in the apocrine secretory cells and is necessary for their sweat secretion, was upregulated in the EMPD samples. This upregulation suggests that Paget cells originate from apocrine secretory cells. Immunohistochemical staining revealed that FOXA1 expression was prevalent in all of the EMPD samples analyzed and was associated with estrogen receptor expression. Our genetic analysis indicates that EMPD frequently involves FOXA1 mutations. FOXA1 is a transcriptional pioneer factor for the estrogen receptor, and the present results suggest that certain treatments for hormone-dependent cancers could be effective for EMPD.

DOI： 10.3390/cancers12040820

Generalized Pustular Psoriasis: Clinical Management and Update on Autoinflammatory Aspects 国際誌

Takeichi, T; Akiyama, M

AMERICAN JOURNAL OF CLINICAL DERMATOLOGY 21 巻 ( 2 ) 頁： 227 - 236 2020年4月

記述言語：英語出版者・発行元：American Journal of Clinical Dermatology

Generalized pustular psoriasis (GPP) is a chronic, systemic inflammatory disease accompanied by high fever and general malaise. Diffuse erythema and swelling of the extremities occur, with multiple sterile pustules all over the body in GPP patients. GPP often relapses over the lifetime and can be life-threatening. Recent discoveries of the underlying molecular genetic basis of many cases of this disorder have provided major advances to clinicians and researchers towards an understanding of the pathomechanism of GPP. However, the therapeutic management of GPP still faces many challenges and much uncertainty, and an evidence-based review summarizing the available clinical data on the management of this heterogeneous disease is needed. The present review addresses challenges regarding the precise clinical diagnosis and evaluation of clinical symptoms in GPP. In addition, we update and briefly summarize the current understanding of molecular pathomechanisms behind GPP as an autoinflammatory keratinization disease. Recent publications have clarified the genetic backgrounds of patients with GPP and ethnic differences in predisposing factors. Although there are ethnic differences in the prevalences of these pathogenic alleles, from recent reports, at most 60.5% (IL36RN), 5.9% (CARD14), and 10.8% (AP1S3) of GPP patients have the mutations/variations of these genes. All the reported biologics studied seemed effective and relatively well tolerated. Although it is difficult to evaluate therapeutic efficacy from studies on just a few cases, recent findings suggest that biologics can be a useful, powerful tool for controlling skin and systemic inflammation in GPP and for improving the quality of life of GPP patients.

DOI： 10.1007/s40257-019-00492-0

Deep phenotyping of ichthyosis follicularis with atrichia and photophobia syndrome associated with MBTPS2 mutations 国際誌

Murase, C; Takeichi, T; Okuno, Y; Ikumi, K; Morita, A; Akiyama, M

JOURNAL OF DERMATOLOGY 47 巻 ( 3 ) 頁： E87 - E88 2020年3月

Successful secukinumab treatment of recalcitrant juvenile generalized pustular psoriasis 国際誌

Nishida, M; Takeichi, T; Kono, M; Imanishi, A; Maekawa, N; Akiyama, M; Fukai, K

JOURNAL OF DERMATOLOGY 47 巻 ( 3 ) 頁： E77 - E78 2020年3月

血清学的に抗BP230抗体単独陽性で、粘膜病変を有した水疱性類天疱瘡の1例

滝奉樹, 武市拓也, 河野通浩, 秋山真志, 杉浦一充, 椙村有里子, 石井文人, 橋本隆

日本皮膚科学会雑誌 130 巻 ( 3 ) 頁： 411 - 412 2020年3月

A case of brain metastasis in HER2-negative extramammary Paget's disease. 査読有り国際誌

Maki-Inoue Y, Takeichi T, Sawada M, Fujitani S, Ohashi A, Akiyama M

European journal of dermatology : EJD 2020年2月

SDR9C7 catalyzes critical dehydrogenation of acylceramides for skin barrier formation 査読有り国際誌

Takeichi, T; Hirabayashi, T; Miyasaka, Y; Kawamoto, A; Okuno, Y; Taguchi, S; Tanahashi, K; Murase, C; Takama, H; Tanaka, K; Boeglin, WE; Calcutt, MW; Watanabe, D; Kono, M; Muro, Y; Ishikawa, J; Ohno, T; Brash, AR; Akiyama, M

JOURNAL OF CLINICAL INVESTIGATION 130 巻 ( 2 ) 頁： 890 - 903 2020年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Clinical Investigation

The corneocyte lipid envelope, composed of covalently bound ceramides and fatty acids, is important to the integrity of the permeability barrier in the stratum corneum, and its absence is a prime structural defect in various skin diseases associated with defective skin barrier function. SDR9C7 encodes a short-chain dehydrogenase/reductase family 9C member 7 (SDR9C7) recently found mutated in ichthyosis. In a patient with SDR9C7 mutation and a mouse Sdr9c7-KO model, we show loss of covalent binding of epidermal ceramides to protein, a structural fault in the barrier. For reasons unresolved, protein binding requires lipoxygenase-catalyzed transformations of linoleic acid (18:2) esterified in ω-O-acylceramides. In Sdr9c7-/- epidermis, quantitative liquid chromatography-mass spectometry (LC-MS) assays revealed almost complete loss of a species of ω-Oacylceramide esterified with linoleate-9,10-trans-epoxy-11E-13-ketone; other acylceramides related to the lipoxygenase pathway were in higher abundance. Recombinant SDR9C7 catalyzed NAD+-dependent dehydrogenation of linoleate 9,10-trans-epoxy-11E-13-alcohol to the corresponding 13-ketone, while ichthyosis mutants were inactive. We propose, therefore, that the critical requirement for lipoxygenases and SDR9C7 is in producing acylceramide containing the 9,10-epoxy- 11E-13-ketone, a reactive moiety known for its nonenzymatic coupling to protein. This suggests a mechanism for coupling of ceramide to protein and provides important insights into skin barrier formation and pathogenesis.

DOI： 10.1172/JCI130675

A novel NCSTN missense mutation in the signal peptide domain causes hidradenitis suppurativa, which has features characteristic of an autoinflammatory keratinization disease

Takeichi, T; Matsumoto, T; Nomura, T; Takeda, M; Niwa, H; Kono, M; Shimizu, H; Ogi, T; Akiyama, M

BRITISH JOURNAL OF DERMATOLOGY 182 巻 ( 2 ) 頁： 491 - 493 2020年2月

Multifaceted Analyses of Epidermal Serine Protease Activity in Patients with Atopic Dermatitis 査読有り国際誌

Nomura, H; Suganuma, M; Takeichi, T; Kono, M; Isokane, Y; Sunagawa, K; Kobashi, M; Sugihara, S; Kajita, A; Miyake, T; Hirai, Y; Yamasaki, O; Akiyama, M; Morizane, S

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES 21 巻 ( 3 ) 2020年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：International Journal of Molecular Sciences

The serine proteases kallikrein-related peptidase (KLK) 5 and KLK7 cleave cell adhesion molecules in the epidermis. Aberrant epidermal serine protease activity is thought to play an important role in the pathogenesis of atopic dermatitis (AD). We collected the stratum corneum (SC) from healthy individuals (n = 46) and AD patients (n = 63) by tape stripping and then measuring the trypsin-and chymotrypsin-like serine protease activity. We also analyzed the p.D386N and p.E420K of SPINK5 variants and loss-of-function mutations of FLG in the AD patients. The serine protease activity in the SC was increased not only in AD lesions but also in non-lesions of AD patients. We found, generally, that there was a positive correlation between the serine protease activity in the SC and the total serum immunoglobulin E (IgE) levels, serum thymus and activation-regulated chemokine (TARC) levels, and peripheral blood eosinophil counts. Moreover, the p.D386N or p.E420K in SPINK5 and FLG mutations were not significantly associated with the SC's serine protease activity. Epidermal serine protease activity was increased even in non-lesions of AD patients. Such activity was found to correlate with a number of biomarkers of AD. Further investigations of serine proteases might provide new treatments and prophylaxis for AD.

DOI： 10.3390/ijms21030913

A juvenile male case of dermatofibrosarcoma protuberans on the breast

Murase, Y; Takeichi, T; Matsumoto, T; Sakakibara, A; Akiyama, M

CLINICAL AND EXPERIMENTAL DERMATOLOGY 45 巻 ( 1 ) 頁： 111 - 113 2020年1月

Case of erythrokeratodermia variabilis successfully treated with narrowband ultraviolet B 国際誌

Okuda, K; Nishida, E; Tori, K; Matubara, A; Sagawa, Y; Takeichi, T; Akiyama, M; Morita, A

JOURNAL OF DERMATOLOGY 47 巻 ( 1 ) 頁： E30 - E31 2020年1月

A patient with bullous pemphigoid with mucosal involvement serologically positive for anti-BP230 autoantibodies only 国際誌

Taki, T; Takeichi, T; Kono, M; Sugiura, K; Sugimura, Y; Ishii, N; Hashimoto, T; Akiyama, M

BRITISH JOURNAL OF DERMATOLOGY 182 巻 ( 1 ) 頁： 221 - 223 2020年1月

Reduced stratum corneum acylceramides in autosomal recessive congenital ichthyosis with a NIPAL4 mutation 査読有り国際誌

Murase, Y; Takeichi, T; Kawamoto, A; Tanahashi, K; Okuno, Y; Takama, H; Shimizu, E; Ishikawa, J; Ogi, T; Akiyama, M

JOURNAL OF DERMATOLOGICAL SCIENCE 97 巻 ( 1 ) 頁： 50 - 56 2020年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Dermatological Science

Background: NIPAL4, encoding the NIPA-like domain containing 4 protein (NIPAL4), is one of the causative genes of autosomal recessive congenital ichthyosis (ARCI). The physiological role of NIPAL4 and the pathogenetic mechanisms of ARCI caused by NIPAL4 mutations remain unclear. Objective: To clarify the changes of ceramide components in the lesional stratum corneum (SC) and the gene expression profile in the lesional skin of an ARCI patient with a novel frameshift mutation in NIPAL4. Methods: We performed ultrastructural and immunohistochemical analyses of the skin. We used RNA sequencing to determine the mRNA expression in the skin of the patient and healthy individuals. We investigated ceramide components using tape stripped SC samples from the patient. Results: mRNA expression profiling in the patient's skin showed significant upregulation of IL-17/TNFα-related genes (IL17C, IL36A, IL36G, S100A7A, S100A9) and psoriasis hallmark genes (VNN3, LCE3D, PLA2G4D), and significant downregulation of lipid-associated genes (GAL, HAO2, FABP7). Ceramide analysis in the patient's SC revealed amounts of CER[NS] with carbon chain-length (C) 32–52 were increased, while amounts of most acylceramide with C66:2 - C72:2 were reduced relatively to those in healthy individuals. After the retinoid treatment, CER[NS] with carbon chains C46–54, CER[EOH] and CER[EOP] increased. Conclusion: IL-17C and IL-36 family cytokines might be involved in the pathogenetic process of ARCI with NIPAL4 mutations. Reduced amounts of the acylceramides in the SC are associated with the skin phenotype due to NIPAL4 mutations. Efficacy of the oral retinoid treatment might be due to restored amounts of CER[EOH] and CER[EOP] in the SC.

DOI： 10.1016/j.jdermsci.2019.12.001